JPH06345757A - Substituted (2-oxo-1-benzimidazolinyl)-piperidines, their preparation, and their use as anti-retroviral agents - Google Patents

Abstract

PURPOSE: To provide new substituted (2-oxo-1-benzimidazolinyl)-piperidines useful as active compounds of antiretroviral agents for protecting HIV-infected cells from virus-induced cell destruction.

CONSTITUTION: A compound of formula I [A is 6-10C aryl which may be optionally substituted up to four times by substituents selected from halogen, carboxyl, NO₂, OH, CF₃, alkyl, alkoxy, cycloalkyl, P(O)-(OR¹)(OR²), CO-R³, CO-NR⁴R⁵, SO₂R⁶, NR⁷R⁸ (R¹ and R² are each H or alkyl; R³ is alkyl, morpholine or phenyl; R⁴ and R⁵ are each H, cycloalkyl, alkyl or the like; R⁶ is phenyl or alkyl; R⁷ and R⁸ are each H, phenyl, alkyl, acryl or the like) or the like], e.g. 1-[2-(2,4- difluorophenyl)amino-2-oxo-ethyl]-4-(2-oxo-1-benzimidazolinyl)piperidine of formula II, is obtained by reacting a compound of formula III (L is a leaving group) with a compound of formula IV.

COPYRIGHT: (C)1994,JPO

Description

Detailed Description of the Invention

The present invention has the general formula (I)

[0002]

[Chemical 3]

[In the formula, A represents an aryl having 6 to 10 carbon atoms, the aryl optionally being halogen, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano, and in each case a straight-chain or an aryl group having 8 carbon atoms or By the same or different substituents selected from the group consisting of branched alkyl, alkoxy, alkoxycarbonyl or alkylthio, by cycloalkyl having 3 to 7 carbons, or by the formula -P (O)-(OR ¹ ) (OR ² ), -C
^{O-R 3, -CO-NR} 4 R 5, -SO 2 R 6, -NR
_{^{7 R 8, -SO 2 NR 9}} R 10, -D-R 11 or -N = N
It may be substituted up to 4 times with the group R ¹² , wherein R ¹ and R ² are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R 1 ³ represents linear or branched alkyl having up to 6 carbon atoms, morpholine or phenyl optionally substituted by halogen, R ⁴ and R ⁵ are the same or different, and hydrogen, carbon number 3-7 cycloalkyl, or a straight-chain or branched alkyl having up to 6 carbon atoms, which alkyl is optionally with phenyl, carboxyl or pyridyl, or straight-chain or branched with up to 6 carbon atoms may be substituted by chain alkoxycarbonyl, or R ⁴ and R ⁵ together with the nitrogen atom, two from the group consisting of S, N and O Having additional heteroatoms at 5-~
A 7-membered saturated heterocycle is formed which, if another nitrogen atom is present in the ring, optionally via this, a benzyl, formyl, carboxyl, direct chain of up to 5 carbon atoms. With the same or different substituents from the group consisting of chained or branched alkoxycarbonyl and benzyloxycarbonyl or of the formula --CH ₂ --CO--N
It may be substituted up to 3 times with the group R ¹³ R ¹⁴ where R ¹³ and R ¹⁴ together with the nitrogen atom are
To form a 7-membered saturated heterocycle, R ⁶ represents phenyl or linear or branched alkyl of up to 6 carbon atoms, R ⁷ and R ⁸ are the same or different, and hydrogen, phenyl , A linear or branched alkyl or acyl having up to 6 carbon atoms in each case, or a compound of the formula -C
(S) -NR ¹⁵ R ^{16 represents} a group, wherein R ¹⁵ represents hydrogen or methyl, and R ¹⁶ represents a linear or branched alkoxycarbonyl having up to 6 carbon atoms, R ⁹ and R ^{10 s} are the same or different, and hydrogen and carbon number 6
Linear or branched alkyl up to, phenyl,
Or a 5- to 6-membered saturated or unsaturated heterocycle having up to 3 further heteroatoms from the group consisting of S, N and O, said ring optionally with hydroxyl or carboxyl or in each case It may be substituted with a linear or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms, and
Represents an oxygen or sulfur atom, R ¹¹ and R ¹² represent the same or different, and optionally phenyl optionally substituted by phenyl]] substituted (2-
It relates to oxo-benzimidazolinyl) -piperidines and their salts, a process for their preparation and their use as antiretroviral agents.

Physiologically acceptable salts of the substituted (2-oxo-benzimidazolinyl) -piperidines can be salts of the substances according to the invention with mineral acids, carboxylic acids or sulphonic acids. . Particularly suitable salts are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,
Benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid,
With propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.

Salts with common bases, for example alkali metal salts (for example sodium or potassium salts),
Alkaline earth metal salts (eg calcium or magnesium salts) or ammonia or organic amines,
For example, diethylamine, triethylamine, ethyldiisopropylamine, procaine, dibenzylamine, N
-Methylmorpholine, dihydroabietylamine, 1-
Ammonium salts derived from ephenamine or methyl-piperidine are also mentioned as salts.

The compounds according to the invention can exist in stereoisomeric forms, which behave as image and mirror image (enantiomers) or do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic and diastereomeric mixtures. Like the diastereomers, the racemic forms can be separated into the stereoisomerically homogeneous components in a known manner.

Heterocycles generally can contain up to 3 sulfur and / or nitrogen atoms as heteroatoms.
Represents a 7-membered, preferably a 5- to 6-membered, saturated or unsaturated ring. Preferred 5- and 6-membered rings are oxygen,
It contains sulfur and / or up to 2 nitrogens. The following may be preferably mentioned: thienyl, furyl, 1,2,4-thiadiazolyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrrolidinyl, thiazolyl, oxazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl,
Tetrazolyl, morpholinyl or thiomorpholinyl.

Suitable compounds of formula (I) are those in which A represents phenyl or naphthyl, each of which is optionally fluorine, chlorine, bromine, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano and in each case the number of carbon atoms. Up to 7 by the same or different substituents selected from the group consisting of linear or branched alkyl, alkoxy, alkoxycarbonyl or alkylthio, by cyclopropyl, cyclopentyl or cyclohexyl, or by the formula -P (O) -(OR ¹ ) (OR ² ),-
^{CO-R 3, -CO-NR} 4 R 5, -SO 2 R 6, -NR 7 R
_{^{8, -SO 2 NR 9 R 10}} , -D-R 11 or -N = NR
^It may be substituted up to 4 times with ¹² groups, where R
¹ and R ² are the same or different, and represent hydrogen or a linear or branched alkyl group having up to 5 carbon atoms, and R ³ is a linear or branched alkyl group having up to 5 carbon atoms; R represents morpholine or phenyl optionally substituted by fluorine, chlorine or bromine, R
⁴ and R ⁵ are the same or different and represent hydrogen, cyclopropyl, cyclopentyl, cyclohexyl or linear or branched alkyl having up to 5 carbon atoms, said alkyl optionally with phenyl, carboxyl or pyridyl, Or, it may be substituted by a linear or branched alkoxycarbonyl having up to 5 carbon atoms, or R ⁴ and R ⁵ together with the nitrogen atom form a piperazine, morpholine or piperidine ring. , Optionally in the case of a piperazine ring, optionally via a nitrogen atom, a group consisting of benzyl, formyl, carboxyl, a linear or branched alkoxycarbonyl having up to 4 carbon atoms and benzyloxycarbonyl. By the same or different substituents from or of the formula --CH ₂ --CO-- It may be substituted up to twice with a group of NR ¹³ R ¹⁴ , where R ¹³ and R ¹⁴ together with the nitrogen atom form a piperazine, piperidine or pyrrolidine ring and R ⁶ is phenyl or carbon. A linear or branched alkyl of up to 5 and R ⁷ and R ⁸ are the same or different and hydrogen, phenyl,
In each case, a linear or branched alkyl or acyl having up to 5 carbon atoms, or a compound of the formula —C (S) —NR ¹⁵ R ¹⁶
Wherein R ¹⁵ represents hydrogen or methyl, and R ¹⁶ represents a linear or branched alkoxycarbonyl having up to 5 carbon atoms, R ⁹ and R ¹⁰ are the same or different, And hydrogen, linear or branched alkyl of up to 5 carbons, phenyl, or pyrimidine, pyridyl, thiazolyl or 1,2,4-thiadiazolyl ring, optionally with hydroxyl or carboxyl or each In any case, it may be substituted with linear or branched alkyl, alkoxy or alkoxycarbonyl having up to 5 carbon atoms,
D is an oxygen or sulfur atom, R ¹¹ and R ¹² are the same or different and are phenyl optionally substituted by fluorine, chlorine or bromine, and salts thereof.

Particularly preferred compounds of general formula (I) are those in which A represents phenyl or naphthyl, each of which is optionally fluorine, chlorine, bromine, iodine, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano and each In each case by the same or different substituents selected from the group consisting of linear or branched alkyl, alkoxy, alkoxycarbonyl or alkylthio having up to 6 carbon atoms, by cyclopropyl, cyclopentyl or cyclohexyl, or by the formula- P (O)-
(OR ¹ ) (OR ² ), -CO-R ³ , -CO-NR ⁴ R ⁵ ,-
_{^{SO 2 R 6, -NR 7 R}} 8, -SO 2 NR 9 R 10, -D-R 11
Alternatively, it may be substituted up to 4 times with a group of —N═NR ¹² , wherein R ¹ and R ² are the same or different, and hydrogen or a linear or branched alkyl group having up to 4 carbon atoms. R ³ represents linear or branched alkyl having up to 4 carbon atoms, morpholine or phenyl optionally substituted by fluorine, chlorine or bromine, and R ⁴ and R ⁵ are the same or And differently and represents hydrogen, phenyl, cyclopropyl, cyclopentyl, cyclohexyl or straight-chain or branched alkyl with up to 5 carbon atoms, said alkyl optionally with phenyl, carboxyl or pyridyl,
Or, it may be substituted with a linear or branched alkoxycarbonyl having up to 4 carbon atoms, or R
⁴ and R ⁵ together with the nitrogen atom are piperazine,
It forms a morpholine or piperidine ring, which, if appropriate, is a piperazine ring, optionally via a nitrogen atom, benzyl, formyl, carboxyl, linear or branched alkoxycarbonyl having up to 3 carbon atoms. And with the same or different substituents from the group consisting of benzyloxycarbonyl or with the formula --CH ₂ --CO--N
It may be substituted up to twice with the group R ¹³ R ¹⁴ , where R ¹³ and R ¹⁴ together with the nitrogen atom form a piperazine, piperidine or pyrrolidine ring, R ⁶
Represents phenyl or straight-chain or branched alkyl having up to 4 carbon atoms, R ⁷ and R ⁸ are the same or different, and hydrogen, phenyl, in each case straight-chain or branched having up to 4 carbon atoms. Branched chain alkyl or acyl,
Or a group of the formula --C (S)-NR ¹⁵ R ¹⁶ where R ¹⁵
Represents hydrogen or methyl, and R ¹⁶ represents a linear or branched alkoxycarbonyl having up to 4 carbon atoms, R ⁹ and R ¹⁰ are the same or different, and hydrogen, a straight chain having up to 4 carbon atoms. Chain- or branched-chain alkyl, phenyl, or pyrimidine, pyridyl, thiazolyl or 1,2,4-thiadiazolyl ring, which is optionally hydroxyl or carboxyl or in each case straight-chain up to 4 carbon atoms Optionally substituted by a branched or branched alkyl, alkoxy or alkoxycarbonyl, D represents an oxygen or sulfur atom, R ¹¹ and R ¹² are the same or different and optionally fluorine, chlorine or bromine. And those salts thereof, which represent optionally substituted phenyl.

General formula (II) A-NH-CO-CH ₂ -L (II) wherein A has the meaning given above and L is a typical leaving group, preferably chlorine or Represents a compound of formula (III) in an inert solvent, optionally in the presence of a base and / or an auxiliary.

[0011]

[Chemical 4]

Is reacted with 4- (2-oxo-1-benzimidazolinyl) -piperidine and the substituents mentioned under A are optionally for example alkylated, acylated, hydrolyzed, hydrogenated, amido A further process for the preparation of the compounds of general formula (I) according to the invention is found, which is characterized in that the derivative is obtained by conventional processes such as hydration or sulphonamidation.

The process according to the invention can be illustrated, for example, by the reaction scheme:

[0014]

[Chemical 5]

Suitable solvents are the customary inert solvents which do not change under the reaction conditions. These are preferably organic solvents such as ethers such as diethyl ether,
Glycol monomethyl ether or glycol dimethyl ether, dioxane or tetrahydrofuran,
Or hydrocarbons such as benzene, toluene, xylene, cyclohexane or mineral oil fractions, or halogeno hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide, ethyl acetate, pyridine, triethylamine Or picoline is included. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, chloroform, dimethylformamide or tetrahydrofuran are particularly suitable.

Bases which can be used for the process according to the invention are generally inorganic or organic bases. These are preferably alkali metal hydroxides such as lithium hydroxide,
Sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide, alkali metal carbonates such as sodium carbonate or potassium carbonate,
Alkaline earth metal carbonates, such as calcium carbonate or cesium carbonate, or alkali metal or alkaline earth metal alkoxides or amides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide, or Lithium diisopropylamide (LDA) or organic amines (trialkyl (C ₁ -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2.2.2] octane (DABCO). 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU),
Pyridine, diaminopyridine, N-methylpiperidine or morpholine are included. It is also possible to use alkali metals, such as sodium, or their hydrides, such as sodium hydride, as base. Triethylamine or N-methylmorpholine are preferred.

In general, the base is 0.05 mol to 10 mol, preferably 1 mol, relative to 1 mol of the compound of formula (III).
It is used in an amount of mol to 2 mol.

The method according to the invention is generally -100.
C. to + 100.degree. C., preferably 0.degree. C. to 80.degree. C., in the temperature range.

The process according to the invention is generally carried out at normal pressure. However, it is also possible to carry out the process under pressure or under reduced pressure (for example in the range from 0.5 to 5 bar).

The auxiliaries used are preferably condensing agents which may be bases, especially when the carboxyl groups are activated and present as anhydrides. Suitable here are the customary condensing agents, such as carbodiimides, such as N, N'-diethyl-, N, N'-diisopropyl or N, N'-dicyclohexylcarbodiimide, N-.
(3-Dimethylaminoisopropyl) -N'-ethyl-
Carbodiimide hydrochloride, N-cyclohexyl-N '-(2-morpholinoethyl) metho-p-toluenesulfonate
A carbodiimide, or a carbonyl compound, such as carbonyldiimidazole, or a 1,2-oxazolium compound, such as 3-ethyl 2-sulfate-5-phenyl-
1,2-Oxazolium or 2-tert-butyl-5-methyl-isoxazolium perchlorate, or an acylamino compound such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or Isobutyl chloroformate, or benzotriazolyloxy-tris (dimethylamino) phosphonium hexafluorophosphate or 1-hydroxybenzotriazole.

Furthermore, for example, alkali metal carbonates such as sodium or potassium carbonate or sodium hydrogen carbonate or potassium hydrogen carbonate, or organic bases such as trialkylamines such as triethylamine, ethyldiisopropylamine, N-ethylmorpholine, N. It is also possible to use -methylpiperidine or N-methylmorpholine. N-methylmorpholine is preferred.

The auxiliaries are in each case 1 mol of the general formula (III)
It is used in an amount of 1.0 mol to 3.0 mol, preferably 1.0 to 1.2 mol, relative to the compound of.

The reaction is carried out at -30 ° C to 100 ° C, preferably 0.
It is carried out in the temperature range from 0 ° C to 30 ° C and at normal pressure.

Suitable solvents for the hydrolysis are water or the customary organic solvents for the hydrolysis. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butanol, or ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

Hydrolysis is generally from -20 ° C to +100.
C., preferably 0.degree. C. to + 80.degree. C., in the temperature range.

Hydrolysis is generally carried out at normal pressure. However, under reduced pressure or increased pressure (eg.
It can also be carried out at 5 to 5 bar).

When carrying out the hydrolysis, the base is generally from 1 to 3 mol, preferably from 1 to 1 mol of ester.
Used in an amount of 1.5 mol. Molar amounts of reactants are particularly preferably used. Hydrolysis of tertiary-butyl esters is generally carried out using acids, such as hydrochloric acid or trifluoroacetic acid, in the presence of one of the above solvents and / or water or mixtures thereof, preferably dioxane, tetrahydrofuran. Or using dichloromethane.

The removal of the amino protecting group can likewise be carried out according to the general procedure using acids such as hydrochloric acid or trifluoroacetic acid.

The removal of the amino protecting group is carried out in a manner known per se, under acidic or basic conditions or in organic solvents, for example using Pd / C, for example ethers such as tetrahydrofuran or dioxane, or It is carried out reductively by catalytic hydrogenation in alcohols such as methanol, ethanol or isopropanol.

The hydrolysis is generally carried out in the temperature range 0 ° C to 80 ° C, preferably 0 ° C to 40 ° C.

The hydrogenation is generally carried out under pressure of 2 to 8 bar, preferably 3 to 5 bar.

In particular in the case of acylamino protecting groups, they can also be removed at room temperature and pressure using one of the abovementioned solvents with a hydride such as lithium aluminum hydride or sodium borohydride.

Removal of the benzyl protecting group is preferably carried out using ammonium formate / palladium / C in ethanol / water in the temperature range 50 ° C. to 100 ° C., preferably 8
It is carried out at 0 ° C. and normal pressure.

Alkylation of amino groups can be accomplished by sulfonate esters or substituted or unsubstituted sulfonic acids (C
₁ -C ₈₎ - dialkyl or (C ₁ -C ₈₎ - diaryl ethers, preferably using using dimethyl methyl iodide or sulfuric acid, or formaldehyde / sodium borohydride, 1 of the ethers In seeds, preferably in tetrahydrofuran, in the presence of an acid.

Alkylation is generally carried out in the above solvent, preferably dimethylformamide, at 0 ° C to + 70 ° C.
It is preferably carried out in a temperature range of 0 ° C to + 30 ° C and atmospheric pressure.

The reduction of the carbonyl function of the general formulas (IV) and (VII) and the partially formed intermediate products containing this group generally uses a reducing agent, for example lithium aluminum hydride, Using a borane solution in tetrahydrofuran or borane-dimethyl sulfide (complex in tetrahydrofuran) at 0 ° C to + 70 ° C,
It is preferably carried out in the temperature range of from + 20 ° C. to + 65 ° C. and normal pressure and then added into the acid. A borane solution in tetrahydrofuran is preferred. Suitable acids for the individual process steps are generally protic acids, such as hydrochloric acid or sulfuric acid. Sulfuric acid is preferably used.

The acid is generally used in an amount of 1 mol to 20 mol, preferably 1 mol to 5 mol, in each case with respect to 1 mol of reactants.

The reaction is generally at -20 ° C to + 80 ° C,
It is preferably carried out in a temperature range of 0 ° C to + 60 ° C.

Generally, the reaction is carried out at normal pressure. However, it is also possible to work under reduced pressure or under increased pressure (for example 0.5 to 5 bar).

The compounds of general formula (III) are known.

The compounds of the general formula (II) are in some cases known or new and have, for example, the general formula (IV) A--NH ₂ (IV) [wherein A has the abovementioned meaning]. The compound is treated in one of the above solvents and bases, preferably in acetonitrile and potassium carbonate, in a temperature range from 0 ° C. to + 80 ° C., preferably + 15 ° C. to + 30 ° C. and at normal pressure. in the general formula (V) T-CO-CH 2 -L (V) [ wherein, L is has the abovementioned meaning and T represents halogen,
And preferably represents chlorine.]

The compounds of the general formulas (IV) and (V) are known.

The inhibitors described herein are HIV proteases and can be used as such for all purposes for which enzyme inhibitors are suitable. This is of use in diagnostics, for example to improve the accuracy and selectivity of enzyme activity measurements. In affinity chromatography they can be used as affinity labels and in research they can be used to elucidate the reaction mechanism and the specificity of enzymatic reactions.

Furthermore, it was surprisingly found that the compounds of the general formula (I) have a very effective action against retroviruses. This has been confirmed by the HIV-specific protease enzyme test.

The results of the examples presented below are found in the following references [Hansen, J. et al. Billich, S .; , Schulz
e), T .; Sukrow, S .; And Melelling, K .; (1988), EM
BO Journal (EMBO Journal), Volume 7,
No. 6, pp. 1785-1791].
Purified HIV protease as measured by the IV test system mimics the cleavage site in the Gag precursor protein and was incubated with a synthetic peptide representing the in vivo cleavage site of HIV protease. The resolution products of synthetic peptides were analyzed by reversed-phase high performance liquid chromatography (R
P-HPLC). The IC ₅₀ values shown relate to the substance concentration which results in a 50% inhibition of protease activity under the above-mentioned test conditions.

HIV Infection in Cell Cultures HIV testing was conducted by Pauwels et al. [Journa of Virological Methods.
l of Virological Method
s), 20 , (1988), 309-321]] with a slight modification.

Normal human blood lymphocytes (PBL) were enriched by Ficoll Hypaque and phytoagglutinin (90 μg / ml) and interleukin-2 (40 U / 40) in RPMI 1640 and 20% fetal bovine serum. ml). Infectious HIV
To infect P. aeruginosa, PBL was pelleted and the cell pellet was then suspended in 1 ml of HIV virus adsorption solution and incubated at 37 ° C. for 1 hour.

On the one hand, HIV-sensitive H9 cells were used in place of normal human blood lymphocytes in order to test the antiviral effect of the compounds according to the invention.

The virus adsorption solution was centrifuged, and the infected cell pellet was added to the growth medium at a concentration of 1 × 10 1 per ml.
⁵ cells were added. Cells infected in this way were pipetted at 1 × 10 ⁴ cells / well.
Added to the wells of a 6-well microtiter plate.

The first vertical row of microtiter plates contained only growth medium and cells that were uninfected but otherwise treated exactly as above (cell control). The second vertical row of microtiter plates contained only HIV-infected cells in the growth medium (virus control). The other wells, starting from the third row of wells of the microtiter plate, contained various concentrations of the compounds according to the invention from which the test substances were diluted 2 ¹⁰ fold in two steps.

The test batches were incubated at 37 ° C. until HIV typical syncytium production occurred in untreated virus controls (3-6 days after infection), which was then evaluated microscopically. Under these test conditions, about 20-
Fifty syncytia occurred in the untreated virus control, whereas the untreated cell control contained no syncytium.

The IC ₅₀ value is determined as the concentration of treated and infected cells when 50% of the virus-induced syncytia (about 10-20 syncytium) are suppressed by the treatment with the compounds according to the invention. Was done.

It has now been found that the compounds according to the invention protect HIV-infected cells from virus-induced cell destruction.

The compounds according to the invention are active compounds useful in human and veterinary medicine for the treatment and prevention of diseases caused by retroviruses.

Scope of Indications for Human Drugs (indi
Cation areas) include: 1.) Treatment and prevention of human retroviral infections.

2.) HIV I (formally HTLV III /
Human immunodeficiency virus called LAV) and HI
Treatment or prevention of diseases caused by VII (AIDS) and its associated phases such as ARC (AIDS related complications) and LAS (lymph node disease syndrome) and immunodeficiency and brain diseases caused by this virus.

3.) Treatment or prevention of HTLV-I or HTLV-II infections.

4.) Treatment or prevention of AIDS-carrier status (AIDS-transmitter status).

Examples of indications for veterinary medicines include: a) madei-visna (in sheep and goats) b) progressive pneumonia virus I (PPB) (sheeps and goats) Middle) c) goat's arthritis encephalitis virus (in sheep and goats) d) zwoegersiekte
Virus (in sheep) e) Infectious anemia virus (equine) f) Infection caused by leukemia virus in cats g) Infection caused by immunodeficiency virus (FIV) in cats h) Immunodeficiency virus in apes (SIV) ) Caused by infectious diseases.

In the range of indications for human medicine, the above items 2, 3 and 4 are preferable.

The present invention contains one or more compounds of formula (I) in addition to a nontoxic, inert, pharmaceutically suitable excipient or one or more compounds of formula (I Included are pharmaceutical formulations of the active compounds of I) as well as methods of making these formulations.

The active compound of formula (I) is present in the abovementioned pharmaceutical formulations in a concentration of approximately 0.1 to 99.5% by weight of the total mixture, preferably approximately 0.5 to 95% by weight. Should.

The pharmaceutical formulations described above may also contain other pharmaceutically active substances besides the compounds of formula (I).

The abovementioned pharmaceutical formulations are prepared in a customary manner according to known methods, for example by mixing one or more active compounds with one or more excipients.

Generally, in both human and veterinary medicine, one or more active compounds are added every 24 hours for about 0.5 to about 500 to obtain the desired results.
It has proved advantageous to use a total amount of body weight of mg / kg, preferably 1 to 100 mg / kg, optionally in several individual dose forms. An individual dose may contain one or more active compounds, preferably about 1 to about 80 mg /
It is contained in an amount of body weight of kg, in particular 1 to 30 mg / kg. However, it may be necessary to deviate from the above dosages, mainly depending on the type and weight of the patient to be treated, and the nature and severity of the disease, the type of formulation and drug administration and the duration or interval between administrations. .

Description of experimental part: TLC system: stationary phase: Merck TLC conditioned silica gel 60F-254 plate, 5x10 cm, layer thickness 0.25.
mm, item No. 5719 Mobile phase ("TLC system" in the test) I: Toluene / Ethyl acetate 1: 1 II: Ethyl acetate / Acetone 3: 1 III: CH ₂ Cl ₂ / Methanol 9: 1 IV: NH ₃ / CH ₂ Cl ₂ / Methanol 0.2: 9: 1 V: HOAc / CH ₂ Cl ₂ / methanol 0.2: 9:
1 VI: glacial acetic acid / n-butanol / H ₂ O 1: 3: 1 HPLC system: HPLC system I: Merck Liclosolve ^R (Mer
ck Lichrosorb ^R ) RP-18 column, 2
50-4, 10 μM, catalyst number (Cat. No) 503
34 Eluent in System A A: pH 7.00 phosphate buffer, Merck item
No. 9439 / H ₂ O 1:50 B: acetonitrile A / B weight / weight 1: 1, flow rate: 2 ml / min, isocratic, detection: 214 nm HPLC system II: column: Nucleosil 120-
5 C18, 5 μM, 125 × 4 mm Eluent: A = 0.01 MH ₃ PO ₄ , B = acetonitrile Eluent program: 0-1 min: 10% B 1-9 min: 10% B / min gradient 9- 13 min: 90% B Flow rate: 2 ml / min Temperature: Room temperature Injection volume: 5 μl Sample: approx. 1 mg / ml Detection: UV diode array at 210 nm Abbreviation index used General analysis method TLC thin layer. Chromatography GC Gas chromatography HPLC High pressure liquid chromatography CC Column chromatography LC Liquid chromatography NMR Nuclear rotation resonance spectrometer (proton) MS Mass spectrometer (electron impact ionization) (+) FAB-MS Rapid atom bombardment mass spectrometer, Positive ion, matrix substance: m-nitrobenzyl alcohol MS -DCI mass spectrometer, chemical ionization reagent NEM N-ethylmorpholine NMM N-methylmorpholine TEA triethylamine TFA trifluoroacetic acid solvent HOAc ethyl acetate DMF dimethylformamide EtOAc acid MeOH methanol EtOH ethanol THF tetrahydrofuran DMSO dimethylsulfoxide HMPT hexamethylphosphoramide CH ₂ Cl ₂ dichloromethane NH ₃ ammonia solution (25% aqueous) Protecting group Boc tert-butoxycarbonyl Z benzyloxycarbonyl DNP dinitrophenyl Fmoc 9-fluorenylmethoxycarbonyl OEt ethyl ester OMe methyl ester

[0067]

EXAMPLES Starting compounds Example I 1-Bromo-2- (2,4-difluorophenyl) amino-2-oxoethane

[0068]

[Chemical 6]

5.16 g (40 mmol) of 2,4-difluoroaniline and 6.3 g (40 mmol) of bromoacetyl chloride in 5.
Treated with 17 g (40 mmol) Hünig base.
After 4 h, the mixture was washed once with twice and water with 1N hydrochloric acid, dried (MgSO _4), and concentrated.

Yield: 7.6 g (70%) ¹ H-NMR (CDCl ₃ ): δ = 4.22 (s, 2
H); 6.92 (m, 2H); 8.20 (m, 1H);
8.40 (broad, NH).

Example II 1-chloro-2- (2-carboxy-4-chlorophenyl) amino-2-oxoethane

[0072]

[Chemical 7]

12.5 g (73 mmol) 2-amino-5-chlorobenzoic acid are first added into 500 ml acetonitrile and 9.0 g (80 ice-bath) keeping the temperature at 20-25 ° C. (Mmol) chloroacetyl chloride with stirring. 22 g (0.16 mol)
Of finely powdered potassium carbonate were then added and the mixture was stirred at room temperature overnight. The batch was adjusted to pH 2 with dilute hydrochloric acid and the acetonitrile stripped on a rotary evaporator. The precipitate was filtered off with suction and washed well with water. The crude product was treated with sodium hydrogen carbonate solution and stirred. Insoluble material is filtered off with suction and the filtrate is adjusted to pH with dilute hydrochloric acid.
Acidified to 2. The product which has precipitated is filtered off with suction and dried.

Yield: 7 g (77.3% of theory) Melting point: 188 ° C. Preparation Examples Example 1 1- [2- (2,4-difluorophenyl) amino-2
-Oxo-ethyl] -4- (2-oxo-1-benzimidazolinyl) piperidine

[0075]

[Chemical 8]

4 g (16 mmol) of bromoacetanilide from Example I and 4.2 g (19 mmol) of 4- (2-oxo-1-benzimidazolinyl) piperidine in 50 ml of dimethylformamide at room temperature 18 Stirred with 2.6 g (19 mmol) potassium carbonate over time. The solid was then filtered off with suction, the filtrate was precipitated between ethyl acetate and water and the aqueous phase was extracted 3 times with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried (MgSO _4), and concentrated. The residue obtained was triturated with ether and the solid filtered off and then recrystallized from methanol.

Yield: 4.8 g (77.6% of theory) TLC system I: R _f = 0.16 HPLC system I: R _t = 4.07 min (+) FAB-MS: m / e = 387M + H Example 2 1- [2- (2-Carboxy-4-chlorophenyl) amino-2-oxoethyl] -4- (2-oxo-1-benzimidazolinyl) piperidine

[0078]

[Chemical 9]

7.94 g (32 mmol) of the compound from Example II and 8.26 g (40 mmol) of 4-
(2-oxo-1-benzimidazolinyl) piperidine (Aldrich) in 120 ml of D
Added first in MF. The mixture was 5.52 g (40 mmol) potassium carbonate and 0.45 g (3 mmol).
Treated with sodium iodide and stirred overnight at room temperature. The batch was diluted with 600 ml H ₂ O and the product was precipitated at pH 5 by the dropwise addition of 33 ml 1N hydrochloric acid. The precipitate is filtered off with suction, stirred with 300 ml of diethyl ether and dried in a high vacuum.

Yield: 12.3 g (89.4% of theory) TLC system I: R _f = 0.36 TLC system III: R _f = 0.25 TL system V: R _f = 0.39 HPLC system I : R _t = 0.93 min HPLC system II: R _t = 4.565 min (+) FAB-MS: m / e = 429/431 (M +
H) Example 3 1- [2- (2-aminophenyl) amino-2-oxoethyl] -4- (2-oxo-1-benzimidazolinyl)
Piperidine

[0081]

[Chemical 10]

4 g (10.12 mmol) of 1- [2-
(2-Nitrophenyl) amino-2-oxoethyl]-
4- (2-Oxo-1-benzimidazolinyl) piperidine was dissolved in 40 ml DMF. After addition of 400 mg of 10% Pd / C (Aldrich), the mixture was hydrogenated at 3 bar until the reaction was complete (TLC). The catalyst was filtered off and all solvent was stripped in high vacuum. The crude product was evaporated several times with methanol. The catalyst obtained was stirred in methanol, filtered off with suction and dried at 30 ° C. in a high vacuum.

Yield: 3.1 g (83.8% of theory) TLC system II: R _f = 0.47 TLC system IV: R _f = 0.51 HPLC system I: R _t = 1.77 min (+ ) FAB-MS: m / e = 366 (M + H) Example 4 1- [2- (4-amino-2-chlorophenyl) amino-2-oxoethyl] -4- (2-oxo-1-benzimidazolinyl) ) Piperidine

[0084]

[Chemical 11]

4.29 g (10 mmol) of 1- [2-
(2-Chloro-5-nitrophenyl) amino-2-oxoethyl] -4- (2-oxo-1-benzimidazolinyl) piperidine, 3.21 g (60 mmol) ammonium chloride, 10 ml water and 60 ml. Methyl glycol was mixed together and the suspension was heated to 110 ° C. with stirring. 20 ml DMF and 3.35
After addition of g (60 mmol) iron charge, the mixture was boiled under reflux for 1 h. The solvent was stripped completely in a high vacuum. The residue was stirred with 150 ml of dichloromethane and 100 ml of water and filtered off. The filtrate was separated in a separating funnel and the aqueous phase was extracted twice more with dichloromethane. The combined organic phases were washed with saturated sodium hydrogen carbonate solution, dried over sodium sulphate and the solvent evaporated in a rotary evaporator.
The solid obtained is stirred with diethyl ether, filtered off with suction and dried.

Yield: 480 mg (12% of theory) The dichloromethane / water-insoluble solid was stirred hot with 150 ml of methanol, filtered off and washed with 50 ml of hot methanol. The filtrate is concentrated to dryness and the residue is triturated with diethyl ether and then filtered off with suction,
And dried. Yield: 2.48 g (62% of theory) Total yield: 2.96 g (74% of theory) TLC (9/1): _Rf = 0.43 HPLC: 2.11 min (+) FAB-MS. : M / e 400/402 M + H The compounds shown in Table 1 were prepared analogously to the steps of Examples 1-4 and the corresponding haloacetamide derivatives and 4- (2-oxo-1-benzimidazolinyl). Produced starting from Piperidine (Aldrich, Jansen). The hemiacetamide derivative used was prepared from the appropriate arylamine and bromo- or chloroacetyl chloride in the same manner as in Examples I and II,
Was synthesized. Some of the haloacetamide derivatives were purchased (Bader). The arylamines used are either commercially available or by known methods (Houben-Weyl)-
Produced-optionally via a nitro compound as precursor. Nitro groups were reduced to amino groups by catalytic hydrogenation or by reaction with base metals such as iron or zinc.

[0087]

[Table 1]

[0088]

[Table 2]

[0089]

[Table 3]

[0090]

[Table 4]

[0091]

[Table 5]

[0092]

[Table 6]

[0093]

[Table 7]

[0094]

[Table 8]

[0095]

[Table 9]

[0096]

[Table 10]

[0097]

[Table 11]

[0098]

[Table 12]

[0099]

[Table 13]

[0100]

[Table 14]

[0101]

[Table 15]

[0102]

[Table 16]

[0103]

[Table 17]

[0104]

[Table 18]

[0105]

[Table 19]

The main features and aspects of the present invention are as follows.

1. General formula (I)

[0108]

[Chemical 12]

[In the formula, A represents an aryl having 6 to 10 carbon atoms, and the aryl is optionally halogen, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano, and in each case, a straight chain having up to 8 carbon atoms or By the same or different substituents selected from the system consisting of branched alkyl, alkoxy, alkoxycarbonyl or alkylthio, by cycloalkyl having 3 to 7 carbon atoms, or by the formula -P (O)-(OR ¹ ) (OR ² ), -C
^{O-R 3, -CO-NR} 4 R 5, -SO 2 R 6, -NR
_{^{7 R 8, -SO 2 NR 9}} R 10, -D-R 11 or -N = N
It may be substituted up to 4 times with the group R ¹² , wherein R ¹ and R ² are the same or different and represent hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, R 1 ³ represents linear or branched alkyl having up to 6 carbon atoms, morpholine or phenyl optionally substituted by halogen, R ⁴ and R ⁵ are the same or different, and hydrogen, carbon number 3-7 cycloalkyl, or a straight-chain or branched alkyl having up to 6 carbon atoms, which alkyl is optionally with phenyl, carboxyl or pyridyl, or straight-chain or branched with up to 6 carbon atoms may be substituted by chain alkoxycarbonyl, or R ⁴ and R ⁵ together with the nitrogen atom, two from the series consisting of S, N and O Having additional heteroatoms at 5-~
A 7-membered saturated heterocycle is formed which, if another nitrogen atom is present in the ring, optionally via this, a benzyl, formyl, carboxyl, direct chain of up to 5 carbon atoms. By the same or different substituents from the system consisting of chain or branched alkoxycarbonyl and benzyloxycarbonyl or of the formula --CH ₂ --CO--N
It may be substituted up to 3 times with the group R ¹³ R ¹⁴ where R ¹³ and R ¹⁴ together with the nitrogen atom are
To form a 7-membered saturated heterocycle, R ⁶ represents phenyl or linear or branched alkyl of up to 6 carbon atoms, R ⁷ and R ⁸ are the same or different, and hydrogen, phenyl , A linear or branched alkyl or acyl having up to 6 carbon atoms in each case, or a compound of the formula -C
(S) -NR ¹⁵ R ^{16 represents} a group, wherein R ¹⁵ represents hydrogen or methyl, and R ¹⁶ represents a linear or branched alkoxycarbonyl having up to 6 carbon atoms, R ⁹ and R ^{10 s} are the same or different, and hydrogen and carbon number 6
Linear or branched alkyl up to, phenyl,
Or a 5- to 6-membered saturated or unsaturated heterocycle having up to 3 further heteroatoms from the system consisting of S, N and O, which ring is optionally by hydroxyl or carboxyl or in each case It may be substituted with a linear or branched alkyl, alkoxy or alkoxycarbonyl having up to 6 carbon atoms, and
Represents an oxygen or sulfur atom, R ¹¹ and R ¹² are the same or different, and represent phenyl optionally substituted by halogen]] substituted (2-
Oxo-benzimidazolinyl) -piperidines and their salts.

2. A represents phenyl or naphthyl,
Each of them is optionally derived from fluorine, chlorine, bromine, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano and in each case straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or alkylthio having up to 7 carbon atoms. With the same or different substituents selected from the group consisting of cyclopropyl,
The cyclopentyl or cyclohexyl, or the formula ^{-P (O) - (OR 1} ) (OR 2), - CO-R 3, -CO-
_{^{NR 4 R 5, -SO 2 R}} 6, -NR 7 R 8, -SO 2 NR
4 depending on the group of ⁹ R ¹⁰ , -D-R ¹¹ or -N = NR ^12.
It may be substituted up to a number of times, wherein R ¹ and R ² are the same or different, and represent hydrogen or a linear or branched alkyl group having up to 5 carbon atoms, and R ^{3 group} having up to 5 carbon atoms. Of straight-chain or branched alkyl, morpholine or phenyl optionally substituted by fluorine, chlorine or bromine, R ⁴ and R ⁵ being the same or different and hydrogen, cyclopropyl, cyclopentyl , Cyclohexyl or straight-chain or branched-chain alkyl having up to 5 carbon atoms, said alkyl being optionally with phenyl, carboxyl or pyridyl, or straight-chain or branched alkoxycarbonyl having up to 5 carbon atoms. may be substituted by, or R ⁴ and R ^5, together with the nitrogen atom, piperazine, Moruhori Or form a piperidine ring, if the ring of the appropriate piperazine ring, optionally via a nitrogen atom, benzyl, formyl, carboxyl, 4 carbon atoms
With the same or different substituents from the system consisting of linear or branched alkoxycarbonyl and benzyloxycarbonyl or of the formula --CH ₂ --CO
It may be substituted up to twice with the group —NR ¹³ R ¹⁴ where R ¹³ and R ¹⁴ together with the nitrogen atom form a piperazine, piperidine or pyrrolidine ring and R ⁶ is phenyl or Linear or branched alkyl having up to 5 carbon atoms, R ⁷ and R ⁸ being the same or different, and hydrogen, phenyl, in each case linear or branched having up to 5 carbon atoms indicates an alkyl or acyl or a group of the formula ^{-C (S) -NR 15 R 16} ,, wherein R ¹⁵ represents hydrogen or methyl and R ¹⁶ is a straight-chain or branched having up to 5 carbon atoms And R ⁹ and R ¹⁰ are the same or different,
And hydrogen, linear or branched alkyl having up to 5 carbon atoms, phenyl, or pyrimidine, pyridyl, thiazolyl or 1,2,4-thiadiazolyl ring,
The ring may be optionally substituted by hydroxyl or carboxyl or in each case by straight-chain or branched alkyl, alkoxy or alkoxycarbonyl having up to 5 carbon atoms, D being an oxygen or sulfur atom, Compounds of general formula (I) above 1 and salts thereof, wherein R ¹¹ and R ¹² are the same or different and represent phenyl optionally substituted by fluorine, chlorine or bromine.

3. A represents phenyl or naphthyl,
Each of them is optionally fluorine, chlorine, bromine, iodine, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano and in each case straight-chain or branched alkyl, alkoxy, alkoxycarbonyl or up to 6 carbon atoms or With the same or different substituents selected from the system consisting of alkylthio, with cyclopropyl, cyclopentyl or cyclohexyl,
Or formula ^{-P (O) - (OR 1} ) (OR 2), - CO-R 3, -
^{CO-NR 4 R 5, -SO} 2 R 6, -NR 7 R 8, -SO 2 N
R ⁹ R ¹⁰ , —D—R ¹¹ or —N═NR ¹² may be substituted up to 4 times, wherein R ¹ and R ² are the same or different, and are hydrogen or up to 4 carbon atoms. R ³ represents a straight-chain or branched alkyl, R ³ is a straight-chain or branched alkyl having up to 4 carbon atoms, morpholine or phenyl optionally substituted by fluorine, chlorine or bromine. R ⁴ and R ⁵ are the same or different, and represent hydrogen, phenyl, cyclopropyl, cyclopentyl, cyclohexyl or a linear or branched alkyl group having up to 5 carbon atoms,
The alkyl may be optionally substituted by phenyl, carboxyl or pyridyl, or by a linear or branched alkoxycarbonyl having up to 4 carbon atoms, or R ⁴ and R ⁵ together with a nitrogen atom. To form a piperazine, morpholine or piperidine ring, which, in the case of a piperazine ring, is optionally a benzyl, formyl, carboxyl, straight chain or branched chain of up to 3 carbon atoms via a nitrogen atom. It may be substituted up to twice with the same or different substituents from the system consisting of chained alkoxycarbonyl and benzyloxycarbonyl or with a group of the formula —CH ₂ —CO—NR ¹³ R ¹⁴ where R ¹³ And R ¹⁴ together with the nitrogen atom form a piperazine, piperidine or pyrrolidine ring, R ⁶ Represents phenyl or linear or branched alkyl having up to 4 carbon atoms, and R ⁷ and R ⁸
Are the same or different and represent hydrogen, phenyl, in each case straight-chain or branched alkyl or acyl having up to 4 carbon atoms, or a group of the formula --C (S)-NR ¹⁵ R ^16. Wherein R ¹⁵ represents hydrogen or methyl, R ¹⁶ represents a linear or branched alkoxycarbonyl having up to 4 carbon atoms, R ⁹ and R ¹⁰ are the same or different, and hydrogen and 4 carbon atoms Up to a straight-chain or branched alkyl, phenyl, or pyrimidine, pyridyl, thiazolyl or 1,2,4-thiadiazolyl ring, said ring optionally with hydroxyl or carboxyl or in each case up to 4 carbon atoms Optionally substituted by a straight chain or branched chain alkyl, alkoxy or alkoxycarbonyl of Wherein R ¹¹ and R ¹² are the same or different and are phenyl optionally substituted by fluorine, chlorine or bromine, compounds of general formula (I) according to 1 above and salts thereof.

4. Formula (II) A-NH-CO -CH 2 -L (II) [ In the formula, A has the meaning indicated above 1-3, and L is a typical leaving group, preferably Is chlorine or bromine,
Represents a compound of
Or in the presence of an auxiliary, the formula (III)

[0113]

[Chemical 13]

Is reacted with 4- (2-oxo-1-benzimidazolinyl) -piperidine and the substituents mentioned under A are optionally substituted, for example with alkylation, acylation, hydrolysis, hydrogenation, amido A method for producing a compound of the above general formula (I), which is characterized in that the compound is made into a derivative by a general method such as cyclization or sulfonamidation.

5. A drug containing one or more of the compounds 1 to 3 above.

6. Use of the compounds of 1 to 3 above for the manufacture of a medicament.

[0117]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/675 9454-4C C07D 401/14 235 417/14 211 C07F 9/6506 9155-4H (72 ) Inventor Siegfried Radaz Germany 51065 Cologne Jacob-Bäme-Sieutrase 21 (72) Inventor Wolfgang Leben Germany 51467 Bergit Shijgrat Bas Ha Siyutres Henzifuen 30 (72) Inventor Hanno Birt Germany 42113 Butppertal Amaus Britsk 128 (72) Inventor Utta Hansen Germany 42115 Butppertar Perlkesi Utrase 98 (72) Inventor Arnold Pessen Germany 42781 Khan Siut Trezemanche Utrase 51

Claims (3)

[Claims] 1. A compound represented by the general formula (I): [In the formula, A represents an aryl having 6 to 10 carbon atoms, and the aryl is optionally halogen, carboxyl, nitro, hydroxyl, trifluoromethyl, cyano, and in each case, a linear or branched chain having up to 8 carbon atoms. With the same or different substituents selected from the group consisting of alkyl, alkoxy, alkoxycarbonyl or alkylthio, with cycloalkyl having 3 to 7 carbons, or with the formula-
^{P (O) - (OR 1} ) (OR 2), - CO-R 3, -CO-NR 4
_{^{R 5, -SO 2 R 6,}} -NR 7 R 8, -SO 2 NR 9 R 10, -
It may be substituted up to 4 times with a group of D-R ¹¹ or -N = NR ¹² , wherein R ¹ and R ² are the same or different and are hydrogen or a straight-chain or branched chain having up to 6 carbon atoms. R ³ represents linear alkyl, R ³ represents linear or branched alkyl having up to 6 carbon atoms, morpholine or phenyl optionally substituted by halogen, R ⁴ and R ⁵ are the same or And differently, and represents hydrogen, cycloalkyl having 3 to 7 carbons, or linear or branched alkyl having up to 6 carbons, said alkyl optionally being phenyl, carboxyl or pyridyl, or having 6 carbons. up to may be substituted by straight-chain or branched alkoxycarbonyl, or R ⁴ and R ⁵ together with the nitrogen atom, S, N Oyo The saturated heterocycle 5- to 7-membered having another Up to two heteroatoms from the group consisting of O forming,
When another nitrogen atom is present in the ring, the ring may optionally be passed through benzyl, formyl, carboxyl, a linear or branched alkoxycarbonyl having up to 5 carbon atoms and It may be substituted up to three times with the same or different substituents from the group consisting of benzyloxycarbonyl or with a group of the formula —CH ₂ —CO—NR ¹³ R ¹⁴ where R ¹³ and R ¹⁴ are nitrogen. Together with the atom, form a 5- to 7-membered saturated heterocycle,
R ⁶ represents phenyl or straight-chain or branched alkyl having up to 6 carbon atoms, R ⁷ and R ⁸ are the same or different and are hydrogen, phenyl, in each case having 6 carbon atoms.
Represents a linear or branched alkyl or acyl or a group of the formula ^{-C (S) -NR 15 R 16} , up to, where R ¹⁵ represents hydrogen or methyl and R ¹⁶ is a carbon number 6
Up to linear or branched alkoxycarbonyl, R ⁹ and R ¹⁰ are the same or different, and are hydrogen, linear or branched alkyl having up to 6 carbon atoms, phenyl, or S , N and O represent a 5- to 6-membered saturated or unsaturated heterocycle having up to 3 further heteroatoms, which ring is optionally hydroxyl or carboxyl or in each case the number of carbon atoms. Optionally substituted by linear or branched alkyl, alkoxy or alkoxycarbonyl up to 6, D represents an oxygen or sulfur atom, R ¹¹ and R ¹² are the same or different and optionally halogen And phenyl, which may be substituted by], and substituted (2-oxo-benzimidazolinyl) -piperidines and These salts. 2. General formula (II) A—NH—CO—CH ₂ —L (II) [wherein A has the meaning indicated in claim 1 and L is a typical elimination A compound of formula (III) embedded image in an inert solvent, optionally in the presence of a base and / or an auxiliary. Of 4- (2-oxo-1-benzimidazolinyl) -piperidine and the substituents mentioned under A are optionally alkylated, acylated, hydrolyzed,
The method for producing a compound of the general formula (I) according to claim 1, which is characterized in that the derivative is prepared by a general method such as hydrogenation, amidation or sulfonamidation. 3. A drug containing one or more of the compounds according to claim 1.